Docetaxel Loaded in Copaiba Oil-Nanostructured Lipid Carriers as a Promising DDS for Breast Cancer Treatment.

Breast cancer is the neoplasia of highest incidence in women worldwide. Docetaxel (DTX), a taxoid used to treat breast cancer, is a BCS-class-IV compound (low oral bioavailability, solubility and intestinal permeability). Nanotechnological strategies can improve chemotherapy effectiveness by promoting sustained release and reducing systemic toxicity. Nanostructured lipid carriers (NLC) encapsulate hydrophobic drugs in their blend-of-lipids matrix, and imperfections prevent drug expulsion during storage. This work describes the preparation, by design of experiments (23 factorial design) of a novel NLC formulation containing copaiba oil (CO) as a functional excipient. The optimized formulation (NLCDTX) showed approximately 100% DTX encapsulation efficiency and was characterized by different techniques (DLS, NTA, TEM/FE-SEM, DSC and XRD) and was stable for 12 months of storage, at 25 °C. Incorporation into the NLC prolonged drug release for 54 h, compared to commercial DTX (10 h). In vitro cytotoxicity tests revealed the antiproliferative effect of CO and NLCDTX, by reducing the cell viability of breast cancer (4T1/MCF-7) and healthy (NIH-3T3) cells more than commercial DTX. NLCDTX thus emerges as a promising drug delivery system of remarkable anticancer effect, (strengthened by CO) and sustained release that, in clinics, may decrease systemic toxicity at lower DTX doses.

Antineoplastics Encapsulated in Nanostructured Lipid Carriers.

Ideally, antineoplastic treatment aims to selectively eradicate cancer cells without causing systemic toxicity. A great number of antineoplastic agents (AAs) are available nowadays, with well-defined therapeutic protocols. The poor bioavailability, non-selective action, high systemic toxicity, and lack of effectiveness of most AAs have stimulated the search for novel chemotherapy protocols, including technological approaches that provide drug delivery systems (DDS) for gold standard medicines. Nanostructured lipid carriers (NLC) are DDS that contain a core of solid and lipid liquids stabilised by surfactants. NLC have high upload capacity for lipophilic drugs, such as the majority of AAs. These nanoparticles can be prepared with a diversity of biocompatible (synthetic or natural) lipid blends, administered by different routes and functionalised for targeting purposes. This review focused on the research carried out from 2000 to now, regarding NLC formulations for AAs (antimetabolites, antimitotics, alkylating agents, and antibiotics) encapsulation, with special emphasis on studies carried out in vivo. NLC systems for codelivery of AAs were also considered, as well as those for non-classical drugs and therapies (natural products and photosensitisers). NLC have emerged as powerful DDS to improve the bioavailability, targeting and efficacy of antineoplastics, while decreasing their toxic effect in the treatment of different types of cancer.

Development of a Versatile Nanostructured Lipid Carrier (NLC) Using Design of Experiments (DoE)-Part II: Incorporation and Stability of Butamben with Different Surfactants.

Nanostructured lipid carriers (NLCs) are typically composed of liquid lipids, solid lipids, and surfactants, enabling the encapsulation of lipophilic drugs. Butamben is a Class II anesthetic drug, according to the Biopharmaceutical Classification System (BCS); it has a log P of 2.87 and is considered a 'brick dust' (poorly water-soluble and poorly lipid-soluble) drug. This characteristic poses a challenge for the development of NLCs, as they are not soluble in the liquid lipid present in the NLC core. In a previous study, we developed an NLC core consisting of a solid lipid (CrodamolTM CP), a lipophilic liquid with medium polarity (SRTM Lauryl lactate), and a hydrophilic excipient (SRTM DMI) that allowed the solubilization of 'brick dust' types of drugs, including butamben. In this study, starting from the NLC core formulation previously developed we carried out an optimization of the surfactant system and evaluated their performance in aqueous medium. Three different surfactants (CrodasolTM HS HP, SynperonicTM PE/F68, and CroduretTM 40) were studied and, for each of them, a 23 factorial design was stablished, with total lipids, % surfactant, and sonication time (min) as the input variables and particle size (nm), polydispersity index (PDI), and zeta potential (mV) as the response variables. Stable NLCs were obtained using CrodasolTM HS HP and SynperonicTM PE/F68 as surfactants. Through a comparison between NLCs developed with and without SRTM DMI, it was observed that besides helping the solubilization of butamben in the NLC core, this excipient helped in stabilizing the system and decreasing particle size. NLCs containing CrodasolTM HS HP and SynperonicTM PE/F68 presented particle size values in the nanometric scale, PDI values lower than 0.3, and zeta potentials above |10|mV. Concerning NLCs' stability, SBTB-NLC with SynperonicTM PE/F68 and butamben demonstrated stability over a 3-month period in aqueous medium. The remaining NLCs showed phase separation or precipitation during the 3-month analysis. Nevertheless, these formulations could be freeze-dried after preparation, which would avoid precipitation in an aqueous medium.

Improved Local Anesthesia at Inflamed Tissue Using the Association of Articaine and Copaiba Oil in Avocado Butter Nanostructured Lipid Carriers.

Unsuccessful anesthesia often occurs under an inflammatory tissue environment, making dentistry treatment extremely painful and challenging. Articaine (ATC) is a local anesthetic used at high (4%) concentrations. Since nanopharmaceutical formulations may improve the pharmacokinetics and pharmacodynamics of drugs, we encapsulated ATC in nanostructured lipid carriers (NLCs) aiming to increase the anesthetic effect on the inflamed tissue. Moreover, the lipid nanoparticles were prepared with natural lipids (copaiba (Copaifera langsdorffii) oil and avocado (Persia gratissima) butter) that added functional activity to the nanosystem. NLC-CO-A particles (~217 nm) showed an amorphous lipid core structure according to DSC and XDR. In an inflammatory pain model induced by λ-carrageenan in rats, NLC-CO-A improved (30%) the anesthetic efficacy and prolonged anesthesia (3 h) in relation to free ATC. In a PGE2-induced pain model, the natural lipid formulation significantly reduced (~20%) the mechanical pain when compared to synthetic lipid NLC. Opioid receptors were involved in the detected analgesia effect since their blockage resulted in pain restoration. The pharmacokinetic evaluation of the inflamed tissue showed that NLC-CO-A decreased tissue ATC elimination rate (ke) by half and doubled ATC's half-life. These results present NLC-CO-A as an innovative system to break the impasse of anesthesia failure in inflamed tissue by preventing ATC accelerated systemic removal by the inflammatory process and improving anesthesia by its association with copaiba oil.

Lipid nanoparticles loaded with butamben and designed to improve anesthesia at inflamed tissues.

The most frequently used local anesthetics (LA) for local infiltration have an ionizable amine in the range of pH 7.6-8.9. Effective anesthesia of inflamed tissues is a great challenge, especially because the induced local acidosis decreases the fraction of the neutral (more potent) LA species in situ. To solve this limitation, the butyl-substituted benzocaine analogue butamben (BTB) - that has no ionizable amine group close to the physiological pH - could be useful if it was not for its low solubility. To overcome the solubility problem, an optimized formulation for BTB using nanostructured lipid carriers (NLC) was developed by a factorial design and characterized using DLS, XRD, DSC and cryo-EM. The release kinetics and cytotoxicity of the new formulation were measured in vitro, while the in vivo tests assessed its effectiveness on healthy and inflamed tissues, in rats. The optimized NLCBTB formulation showed desirable physicochemical properties (size = 235.6 ± 3.9 nm, polydispersity = 0.182 ± 0.006 and zeta potential = -23.6 ± 0.5 mV), high (99.5%) encapsulation efficiency and stability during 360 days of storage at room temperature. NLCBTB prolonged the release of butamben and decreased its in vitro cytotoxicity without inducing any in vivo toxic alteration. In the inflammatory hyperalgesia model, the NLCBTB formulation showed potential for the management of inflammatory pain, displaying greater analgesic effectiveness (40%) and a prolonged effect.

Injectable in situ forming nanogel: A hybrid Alginate-NLC formulation extends bupivacaine anesthetic effect.

Finding an ideal anesthetic agent for postoperative pain control, with long action and low side effects, is still a challenge. Local anesthetics have potential for such application if their time of action is improved. This work introduces a new hybrid formulation formed by the association of a nanostructured lipid carrier with a biopolymeric system to encapsulate bupivacaine (BVC). The hybrid formulation was physicochemical and structurally characterized by DLS, TEM, DSC, XRD and FTIR-ATR, and it remained stable for 12 months at room temperature. In vivo analgesia and imaging tests showed that the hybrid system was able to modulate the release, and to increase the concentration of BVC at the site of action, by forming a nanogel in situ. Such nanogel improved over 5 times (>24 h) the anesthesia duration, when compared to free BVC at clinical (0.5%) doses. Therefore, this novel in situ-forming nanogel shows great potential to be used in postsurgical pain control, improving the action of BVC, without losing its versatility of (infiltrative) application.

Articaine in functional NLC show improved anesthesia and anti-inflammatory activity in zebrafish.

Anesthetic failure is common in dental inflammation processes, even when modern agents, such as articaine, are used. Nanostructured lipid carriers (NLC) are systems with the potential to improve anesthetic efficacy, in which active excipients can provide desirable properties, such as anti-inflammatory. Coupling factorial design (FD) for in vitro formulation development with in vivo zebrafish tests, six different NLC formulations, composed of synthetic (cetyl palmitate/triglycerides) or natural (avocado butter/olive oil/copaiba oil) lipids were evaluated for loading articaine. The formulations selected by FD were physicochemically characterized, tested for shelf stability and in vitro release kinetics and had their in vivo effect (anti-inflammatory and anesthetic effect) screened in zebrafish. The optimized NLC formulation composed of avocado butter, copaiba oil, Tween 80 and 2% articaine showed adequate physicochemical properties (size = 217.7 ± 0.8 nm, PDI = 0.174 ± 0.004, zeta potential = - 40.2 ± 1.1 mV, %EE = 70.6 ± 1.8) and exhibited anti-inflammatory activity. The anesthetic effect on touch reaction and heart rate of zebrafish was improved to 100 and 60%, respectively, in comparison to free articaine. The combined FD/zebrafish approach was very effective to reveal the best articaine-in-NLC formulation, aiming the control of pain at inflamed tissues.